Derivatives of 3-hydroxyazabenzo(B)thiophene useful as 5-lipoxygenase inhibitors

ABSTRACT

3-Hydroxyazabenzo[b]thiophene derivatives having optionally 2-aryl, 2-aralkyl, 2-alkyl or 2-alkenyl substituents were prepared by, among other methods, ring closure of an appropriately substituted benzylthio-alkoxycarbonyl-pyridine. These compounds are found to be useful in the treatment of pain, fever, inflammation, arthritic conditions, asthma, allergic disorders, skin diseases such as psoriasis and atopic eczema, cardiovascular disorders, inflammatory diseases and other leukotriene mediated diseases.

BACKGROUND OF THE INVENTION

This invention relates to 3-hydroxyazabenzothiophenes having the2-position substituted with an optionally substituted aryl, aralkyl,alkyl, or alkenyl group, for example,3-acetyloxy-7-aza-2-phenyl-benzo[b]thiophene.

These novel azabenzothiophenes are found to be either specific5-lipoxygenase inhibitors or dual 5-lipoxygenase/cyclooxygenaseinhibitors and are therefore useful in the treatment of prostaglandinand/or leukotriene mediated diseases.

Among various potent biological mediators derived from the oxygenationof arachidonic acid, prostaglandins and leukotrienes have been linked tovarious diseases. Notably, the biosynthesis of prostaglandins has beenidentified as a cause of inflammation, arthritic conditions and pain,and the formation of leukotrienes has been connected to immediatehypersensitivity reactions and pro-inflammatory effects. It has beenestablished that arachidonic acid undergoes oxygenation via two majorenzymatic pathways:

(1) The pathway catalyzed by the enzyme cyclooxygenase; and

(2) The pathway catalyzed by the enzyme 5-lipoxygenase.

Interruption of these pathways by enzyme inhibition has been exploredfor effective therapy. For example, non-steroidal anti-inflammatorydrugs (NSAID's) such as aspirin, indomethacin and diflunisal are knowncyclooxygenase inhibitors which inhibit the process wherein arachidonicacid is oxygenated via cyclooxygenase to prostaglandins andthromboxanes.

Recently, it has been observed that certain leukotrienes are responsiblefor diseases related to immediate hypersensitivity reactions such ashuman asthma, allergic disorders, and skin diseases. In addition,certain leukotrienes and derivatives thereof are believed to play animportant role in causing inflammation (B. Samuelsson, Science, 220, 568(1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).

DETAILED DESCRIPTION OF THE INVENTION A. SCOPE OF THE INVENTION

The present invention relates to novel compounds of formula (I):##STR1## or a pharmaceutically acceptable salt thereof wherein

N can be at carbon 4, 5, 6 or 7;

X₁, X₂ and X₃ independently are:

(1) Q, where Q is H; loweralkyl, especially C₁₋₆ alkyl; haloloweralkyl,especially fluoro or chloro C₁₋₆ alkyl such as trifluoromethyl; phenylof formula ##STR2## or naphthyl; or imidazole of formula ##STR3##wherein R³ is H, C₁₋₆ alkyl, C₆₋₁₄ aryl, C₃₋₆ cycloalkyl or halo C₁₋₆alkyl;

(2) halo, especially chloro, fluoro, or bromo;

(3) loweralkenyl, especially C₂₋₆ alkenyl, such as ethenyl and allyl;

(4) loweralkynyl, especially C₂₋₆ alkynyl, for example, ethynyl orn-butynyl; ##STR4## wherein q is an integer of 0 to 2; (6) --OQ;

(7) --CHQCOQ¹, where Q¹ is Q and can be the same as or different from Q;

(8) --CHQ(CO)OQ¹ ;

(9) --CH₂ SQ or --CHQSQ¹ ;

(10) --CH₂ OQ or --CHQOQ¹ ;

(11) --COQ;

(12) --(CO)OQ;

(13) --O(CO)Q;

(14) --NQQ¹ ;

(15) --NQ(CO)Q¹ ;

(16) --NQSO₂ Q¹ ;

(17) --SO₂ NQQ¹ ;

(18) --SO₃ Q

(19) --CN;

(20) --NO₂ ;

(21) --CONQQ¹ ;

(22) --NO;

(23) --CSQ;

(24) --CSNQQ¹ ;

(25) --CF₂ SQ;

(26) --CF₂ OQ;

(27) --NQCONHQ¹ or --NQCONQ¹ Q² ; or

(28) -methylenedioxy;

R¹ is

(a) H;

(b) loweralkyl, especially C₁₋₆ alkyl, such as methyl, ethyl, i-propyl,n-propyl, t-butyl, n-butyl, i-pentyl, n-pentyl, and n-hexyl;

(c) aryl, especially C₆₋₁₄ aryl, e.g., naphthyl, anthryl, phenyl orsubstituted phenyl of formula ##STR5## (d) lowercycloalkyl, especiallyC₃₋₆ cycloalkyl, e.g., cyclopropyl, cyclopentyl, and cyclohexyl;

(e) haloloweralkyl, especially halo C₁₋₆ alkyl, e.g. --CF₃, --CHF₂,--CF₂ CF₃ ;

(f) heteroaryl or heteroaryl substituted with X₁ and X₂ especiallypyridyl imidazolyl, pyrryl, furyl or thienyl wherein X₁ and X₂ are aspreviously defined;

(g) benzyl of formula ##STR6## (h) loweralkynyl, especially C₁₋₆alkynyl, such as HC.tbd.C--; CH₃ --C.tbd.C--, or HC.tbd.C--CH₂ --;

(i) loweralkenyl, especially C₁₋₆ alkenyl, such as CH₂ ═CH--, CH₃CH═CH--, CH₂ ═CHCH₂ --, CH₃ CH═CH--CH₂ --, (CH₃)₂ C═CH-- or --CH═CHCOOR²wherein R² is loweralkyl, especially C₁₋₆ alkyl,

(j) aralkenyl of formula ##STR7## wherein Y₁ and Y₂ independently arephenyl and heteroaryl as previously defined;

(k) aralkynyl of formula

    --C.tbd.C--Y.sub.1

(1) (CH₂)_(m) (CO)R³ wherein m is an integer of 1-6 and R³ is H, C₁₋₆alkyl, C₆₋₁₄ aryl, C₃₋₆ cycloalkyl or haloC₁₋₆ alkyl;

(m) --(CH₂)_(m) OR³ ;

(n) --(CH₂)_(m) O(CO)OR³ ;

(o) --(CH₂)_(m) NR³ R⁴ wherein R⁴ can be the same or different from R³and R⁴ is R^(3;)

(p) --(CH₂)_(m) --NR³ (CO)R⁴ ;

(q) --(CH₂)_(m) (CO)OR³ ; or

(r) ##STR8## R is (a) H;

(b) --(CO)R³ ;

(c) --(CO)OR³ ;

(d) --(CO)NR³ R⁴ ;

(e) --(CO)SR³ ;

(f) --(CH₂)_(m) COR³ ;

(g) --(CH₂)_(m) OR³ ;

(h) --(CH₂)_(m) O(CO)OR³ ;

(i) --(CH₂)_(m) NR³ R⁴ ;

(j) --(CH₂)_(m) NR³ (CO)R⁴ ;

(k) loweralkyl as previously defined;

(l) lowercycloalkyl as previously defined; or

(m) haloloweralkyl as previously defined; and

p is 0 or 1.

Preferably, an enzyme inhibitor of this invention is of formula:##STR9## wherein X₁, X₂, R and R¹ are as previously defined.

More preferably, an enzyme inhibitor of this invention is of formula:##STR10## wherein

R is H or (CO)CH₃ ;

R¹ is phenyl substituted with X₂ or pyridyl;

X₁ is

(a) H;

(b) C₁₋₆ alkyl;

(c) halo;

(d) halo-C₁₋₆ -alkyl, e.g. CF₃ ;

(e) CN;

(f) --(CO)OR³ ;

(g) --OC₁₋₆ alkyl;

(h) phenyl-CH(OH)--;

(i) CH₂ S-Aryl; or

(j) --CH₂ S--(CH₂)_(x) -aryl;

wherein x is 1 to 4;

X₂ is

(a) H:

(b) -methylenedioxy;

(c) halo-C₁₋₆ alkyl, e.g., CF₃ ;

(d) halo;

(e) CN;

(f) --OC₁₋₆ alkyl;

(g) --OC₁₋₆ alkylphenyl;

(h) --(CO)OR³ ;

(i) C₁₋₆ alkyl; or

(g) NO₂. B. Preparation of the compounds of the invention

The compounds of the present invention can be divided into foursubclasses depending upon the position of the aza substitution in thebenzo[b] thiophene ring (position 4, 5, 6, or 7). General procedures,specific examples, and tables of physical data are given below.##STR11##

Compounds of this subclass are prepared by base-catalyzed (sodiumhydride, potassium t-butoxide, lithium diisopropylamide, or the like)ring closure of an appropriately substituted alkyl or benzyl2-arylmethylthionicotinate, for example, compound 1 in a solvent, suchas dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidinone,tetrahydrofuran, or the like, at a temperature of from ambient to 100°C. for a period of six to twenty-four hours. The required alkyl orbenzyl 2-arylmethylthionicotinates (1) are prepared by base-catalyzed(cesium carbonate, diazabicyclo[5,4,0]undec-7-ene(DBU), triethylamine,or the like) esterification of an appropriately substituted2-arylmethylthionicotinic acid in a solvent such as acetonitrile,tetrahydrofuran, N,N-dimethylformamide, or the like in the presence of aslight excess of alkyl chloride, bromide, or iodide or benzyl chlorideor bromide, at a temperature of from ambient to 65° C. for a period ofsix to twenty-four hours. The methyl nicotinates may also be prepared bytreatment with carbonyldiimidazole in a solvent such asN,N-dimethylformamide followed by treatment with sodium methoxide inmethanol. The required 2-arylmethylthionicotinic acids (2) are preparedby treatment of the known nicotinic acids (3) with two equivalents ofbase, such as sodium methoxide in methanol, sodium hydride inN,N-dimethylformamide, or potassium t-butoxide in tetrahydrofuran or thelike, at a temperature of from -5° to 25° C. followed by treatment withthe appropriately substituted arylmethyl chloride or bromide at ambienttemperatures for a period of time from one to 24 hours.

As shown below in scheme (b), selective modification of the 6-positionof the pyridine ring, when it is appropriate, can be obtained bytreatment of a 2-aryl-3-methoxymethoxy-7-azabenzo[b]thiophene with anucleophile, such as n-butyllithium or t-butyllithium, in a solvent suchas tetrahydrofuran at a temperature from -78° C. to room temperature for1-24 hours. Alternatively, as shown in scheme (c), modification can beeffected by lithiation of the 6-position with a non-nucleophilic basesuch as trityllithium, followed by treatment with an electrophile, suchas benzaldehyde. ##STR12##

Substitution in the pyridine ring is also effected via oxidation of the3-acetyloxy-2-arylbenzo[b]thiophene derivatives (4) to theircorresponding N-oxides (5) by treatment with an oxidizing agent, such asm-chloroperbenzoic acid or the like in a solvent such asdichloromethane, tetrahydrofuran, or the like at a temperature of fromambient to 65° C. for a period of time of from one to 24 hours.##STR13##

Treatment of the pyridine N-oxide derivatives (5) with an acid chloride,such as phosphoryl chloride or the like, affords a mixture of the4-chloro (6) and 6-chloro (7) derivatives, which function asintermediates to other pyridine ring substituted analogs vianucleophilic displacement reactions and the like. Representativecompounds of the 7-aza subclass are listed in Table I.

                  TABLE I                                                         ______________________________________                                        2-ARYL-7-AZA-BENZO[b]THIOPHENES                                                ##STR14##                                                                    X.sub.2      R           m.p.                                                 ______________________________________                                        H            H           234-235°                                      3-OCH.sub.3  H           187-189°                                      4-OCH.sub.3  H           209-212°                                      4-OCH.sub.3  COCH.sub.3  140-141°                                      2-OCH.sub.3  H           142-144°                                      H            COCH.sub.3    86-87.5°                                    4-CF.sub.3   H           261-264°                                      4-F          COCH.sub.3  152-154°                                      4-CF.sub.3   COCH.sub.3  133-134°                                      H            COCH.sub.2 OCH.sub.3                                                                      88-91°                                        ______________________________________                                    

    ______________________________________                                         ##STR15##                                                                            R   m.p.                                                              ______________________________________                                                H   245-248° (d)                                                       Ac  115-116°                                                   ______________________________________                                    

    ______________________________________                                         ##STR16##                                                                            R     m.p.                                                            ______________________________________                                                CH.sub.2 OMe                                                                        54°                                                              H     181-183°                                                         Ac    128-129°                                                 ______________________________________                                    

II. 2-Aryl-6-Azabenzo [b]thiophenes

As shown below in scheme (e), compounds of this subclass are prepared bytreatment of a 3-halo-4-cyanopyridine (8) with the appropriatelysubstituted arylmethylmercaptide, which was obtained by treatment of themercaptan with a base, such as sodium methoxide, sodium hydride,triethylamine, lithium diisopropylamide, etc., in a solvent such asacetonitrile, N,N-dimethylformamide, dimethyl-sulfoxide, tetrahydrofuranat temperatures from -78° C. to 65° C. for 30 minutes to 24 hours. Thederived 3-arylmethylthio-4-cyanopyridines are saponified to thecorresponding acids with base, such as aqueous sodium hydroxide orpotassium hydroxide, followed by acidification. The acids are esterifiedeither by treatment with carbonyldiimidazole in tetrahydrofuran ordimethylformamide for 1-6 hours at 0°-65° C. followed by treatment withmethanol for 1-6 hours at room temperature or by heating with methanol,dimethoxypropane, and sulfuric acid under reflux for 12-36 hours. Thederived methyl-3-arylmethylthiopyridine4-carboxylates (11) arering-closed to the 2-aryl-3-hydroxy-6-azabenzo[b]thiophenes (12) andfurther modified as described for the 7-aza series. ##STR17##

Alternatively, as shown below in scheme (f), the 6-aza series may bederivatized selectively at the 7-position by lithiation withn-butyllithium-TMEDA complex to generate the 7-lithio species, whichthen can be reacted with an electrophile such as benzaldehyde. ##STR18##

III. 2-ARYL-5-AZA-BENZO[b]THIOPHENES

Compounds of this subclass are prepared in an analogous fashion as thatdescribed for the 7-aza series, but employing as starting material4-mercaptonicotinic acid obtained by the process set forth in L. Katz,M. S. Cohen, and W. Schroeder, U.S. Pat. No. 2,824,876 (2-25-58).

Alternatively, the 5-aza-benzol[b]thiophenes can be prepared from4-chloronicotinic acid by the process set forth in W. C. J. Ross, J.Chem. Soc. (C), 1816 (1966). Displacement of the chloro group by anappropriately substituted arylmethyl mercaptide is carried out in asolvent such as N,N-dimethylformamide, dimethylsulfoxide,tetrahydrofuran, or the like, at a temperature of from 0° to 65° C. fora period of from 30 minutes to 24 hours. The derived4-aryl-methylthionicotinic acids are then esterified, ring closed andfurther modified as described for the 7-aza series to the desired2-aryl-3-hydroxy-5-aza-benzo[b]thiophenes (9). ##STR19##

IV. 2-Aryl-4-Azabenzo[b]thiophenes

As illustrated by the following scheme (h), compounds of this subclassare prepared from available methyl 3-hydroxypyridine-2-carboxylates(13). The 3-hydroxy compounds are converted to the 3-mercaptans bytreatment of (13) with N,N-dimethyl-aminothiocarbamoyl chloride and abase, such as sodium or potassium hydroxide, in aqueous tetrahydrofuranor dioxane for 1-6 hours at room temperature. The resultingthiocarbamates are isomerized by heating at temperatures between160°-240° C. in a solvent such as o-dichlorobenzene orm-dimethoxybenzene for 1-8 hours. The N,N-dimethylaminocarbamoylmercaptans are deblocked by treatment with sodium methoxide-methanol atroom temperature for 10-60 minutes and the resulting mercaptides arealkylated with an arylmethylchloride in a solvent such astetrahydrofuran, N,N-dimethylformamide, or dioxane at room temperaturefor 1-24 hours. Ring closure is effected by treatment with base, such aslithium diisopropylamide in tetrahydrofuran at 78° C. or by the methodsdescribed for the 7-aza series. ##STR20##

The following examples illustrate but do not limit the presentinvention.

EXAMPLE 1 Preparation of7-aza-3-hydroxy-2-(3-methoxyphenyl)benzo[b]thiophene Step A: Preparationof 2-(3-Methoxybenzylthio)-nicotinic acid

A suspension of 4.65 g (0.03 mole) of 2-mercaptonicotinic acid in 100 mlof methanol was cooled in ice as 3.24 g (0.06 mole) of sodium methoxidewas added. The resulting solution was left at ice - temperature as 4.68g (0.03 mole) of 3-methoxybenzyl chloride was added over 5 minutes. Thereaction mixture was stirred for 14 hours and the reaction set solid.The addition of 50 ml of water caused solution and an excess of aceticacid precipitated 7.55 g (92% of theory) of2-(3-methoxybenzylthio)nicotinic acid. Recrystallization was effectedfrom ethyl acetate; m.p. 156-157° C.

Anal.: Calc'd. for C₁₄ H₁₃ NO₃ S. C=61.09; H=4.76, N=5.09. Found:C=61.19, H=4.83, N=5.22.

Step B: Preparation of Methyl 2-(3-methoxy benzylthio)nicotinate

A suspension of 7.15 g (0.026 mole) of 2-(3-methoxybenzylthio)nicotinicacid in 75 ml of dry acetonitrile was treated with 3.95 g (0.026 mole)of 1,8-diazabicyclo[5,4,0]-under-7-ene (DBU). A solution formed and 4.26g (0.030 mole) of methyl iodide was added over one minute. After keepingthe reaction mixture at room temperature for 24 hours, the solution wasevaporated in vacuo. The residue was partitioned between 100 ml of etherand 50 ml of water. The ether layer was washed with 50 ml of H₂ O,dried, and evaporated to a small volume. The addition of hexane withcooling yielded 6.9 g (92% of theory) of methyl2-(3-methoxybenzylthio)nicotinate; m.p. 69°-70° C.

Anal.: Calc'd. for C₁₅ H₁₅ NO₃ S.

C=62.28, H=5.23, N=4.84. Found: C=62.09, H=5.28, N=4.83.

Step C: Preparation of 7-Aza-3-hydroxy-2-(3-methoxyphenyl)-benzo[b]thiophene

To a stirred solution of 5.78 g (0.02 mole) of methyl2-(3-methoxybenzylthio)nicotinate in 30 ml of dry N-methylpyrrolidinonewas added 800 mg (0.02 mole) of 60% sodium hydride dispersion. Thereaction was stirred at room temperature for 14 hours then poured intoice water. The solution was extracted with 50 ml of hexane, and theaqueous layer was treated with an excess of acetic acid to precipitate7-aza-3-hydroxy-2-(3-methoxyphenyl)benzo[b]thiophene; yield 4.4 g (86%of theory). The crude product was recrystallized from ethyl acetate;m.p. 187°-189° C. Anal.: Calc'd. for C₁₄ H₁₁ NO₂ S. C=65.37, H=4.31,N=5.44. Found: C=65.31, H=4.35, N=5.40.

EXAMPLE 2 3-Acetoxy-6-(1,1-dimethylethyl)-2-phenyl-7-azabenzo[b]-thiophene Step A: Preparation of 2-Phenylmethylthionicotinic acid

A sample of 15.5 g (100 mmol) of 2-mercaptonicotinic acid was dissolvedin 50 mL of 4.1M sodium methoxide in methanol and 100 mL of methanol. Tothis was added 18.8 g (110 mmol) of benzyl bromide and the solution wasstirred at room temperature for 3 hours. Then 250 mL of water was addedand the solution was acidified to pH 7 with glacial acetic acid. Theprecipitate was collected, washed with water, and dried to afford 22.3 g(91%) of white solid.

Step B: Preparation of Methyl 2-phenylmethylthionicotinate

A solution of 18.3 g (75 mmol) of 2-phenylmethylthionicotinic acid and16.2 g (100 mmol) of carbonyldiimidazole in 250 mL of drydimethylformamide was stirred at room temperature for 2 hours. Thesolution was cooled to 0° and 25 mL of 4M sodium methoxide in methanolwas added. After warming to room temperature the solution waspartitioned between ether and water and the aqueous layer was washedwith two portions of ether. The ether extracts were washed with brine,dried over MgSO₄, and concentrated. The residue was crystallized fromether-hexane to afford 17.4 g (89%) of fine white needles, which wasused in the next step without further purification.

Step C: Preparation of 3-Hydroxy-2-phenyl-7-azabenzo[b]thiophene

A suspension of 12.9 g (50 mmol) of methyl 2-phenylmethylthionicotinateand 2.6 g (110 mmol) of sodium hydride in 100 mL of dryN,N-dimethylformamide was stirred for 4 hours at room temperature. Thesolution was diluted with 200 mL water and acidified with glacial aceticacid. The precipitate was collected, washed with water, and dried toafford 10.6 g (93%) of a white crystalline solid to be used in the nextstep.

Step D: Preparation of 3-Methoxymethoxy-2-phenyl-7-azabenzothiophene

A suspension of 4.54 g (20 mmol) of3-hydroxy-2-phenyl-7-azabenzo[b]thiophene and 2.75 g (22 mmol) ofpotassium t-butoxide in 50 mL of tetrahydrofuran was stirred until thesolid dissolved. Then 2.0 g (25 mmol) of chloromethyl methyl ether wasadded and the solution was stirred at room temperature for 2 hours. Thesolution was partitioned between ether and water and the aqueous layerwas washed with two portions of ether. The ether extracts were washedwith brine, dried over MgSO₄, and concentrated to 4.33 g (80%) of an oilthat crystallized upon standing, m.p. 54° C.

Step E: Preparation of6-(1,1-dimethylethyl)-3-hydroxy-2-phenyl-7-azabenzo[b]thiophene

A solution of 2.72 g (10.0 mmol) of3-methoxymethoxy-2-phenyl-7-azabenzothiophene in 20 mL of drytetrahydrofuran was cooled to -78° C. To this was added 11 mL of a 1.0Msolution of t-butyllithium in hexane and the solution was allowed towarm to room temperature. The solution was quenched with methanol andstirred in air for 60 minutes, then partitioned between ether and water.The aqueous layer was washed with two portions of ether and the combinedextracts were washed with brine, dried, and concentrated to an oil. Theoil was dissolved in 10 mL methanol and 10 mL of 2M HCl and stirred atroom temperature for 24 hours. The solution was partitioned betweenether and water and the ether layer dried and concentrated.Recrystallization from ether-hexane afforded 2.43 g (84%) of pale yellowneedles, m.p. 181°-183° C.

Step F: Preparation of3-Acetoxy-6-(1,1-dimethylethyl)-2-phenyl-7-azabenzo[b]thiophene

A solution of 1.42 g (5 mmol) of6(1,1-dimethylethyl)-3-hydroxy-2-phenyl-7-azabenzo[b]thiophene and 1.42g sodium acetate in 20 mL of acetic anhydride was heated at reflux for 1hour. The solution was concentrated and the residue was partitionedbetween ether and water. The ether layer was washed with sodiumbicarbonate solution and brine, dried and concentrated. The residue wascrystallized from ether-hexane to afford 1.49 g (91%) of fine whiteneedles, m.p. 128°-9° C.

EXAMPLE 3 3-Hydroxy-2-(4-methoxyphenyl)-6-azabenzo[b]thiophene Step A:Preparation of 4-Cyano-3-(4-methoxyphenyl)methylmercaptopyridine

A solution of 6.2 g (40 mmol) of p-methoxybenzylmercaptan in 9.8 mL of4.4M sodium methoxide in methanol was added dropwise to a solution of5.52 g (40 mmol) of 3-chloro-4-cyanopyridine in dry acetonitrile thathas been cooled in an ice bath. After addition was complete the solutionwas allowed to warm to room temperature over 2 hours. The solvent wasconcentrated and the residue was partitioned between dichloromethane andwater. The aqueous layer was extracted with two portions ofdichloromethane and the combined extracts were washed with brine, dried(MgSO₄) and concentrated to afford 6.1 g (60%) of a pale yellowcrystalline solid, m.p. 80°-81° C.

Step B: Preparation of3-(4-methoxyphenyl)methylthiopyridine-4-carboxylic acid

A solution of 6.0 g (23.4 mmol) of4-cyano-3-(methoxyphenyl)methylthiopyridine in 15 mL of 6M NaOH washeated under reflux for 6 hours. The solution was cooled, and acidifiedwith glacial acetic acid. The precipitate was collected by filtrationand triturated with two portions of cold ether to afford 6.0 g (94%) ofwhite crystals, m.p. 250° C. (decomp.).

Step C: Preparation of Methyl 3-(4-methoxyphenyl)methylthiopyridine-4-carboxylate

A solution of 4.9 g (17.8 mmol) of3-(4-methoxyphenyl)methylthiopyridine-4-carboxylic acid and 4.9 g (30mmol) of carbonyldiimidazole in 50 mL of dry N,N-dimethylformamide wasstirred at 0° C. for 10 minutes and then allowed to warm to roomtemperature. After 2 hours the solution was cooled to 10° C. andquenched with 20 mL of methanol. The mixture was stirred for 2 hours andthen the solvent was concentrated. The residue was partitioned betweenether and water and the aqueous layer was extracted with three portionsof ether. The ether extracts were dried (MgSO₄) and concentrated toafford 5.1 g (93%) of a crystalline solid, m.p. 99°-100° C.

Step D: Preparation of3-Acetoxy-2-(4-methoxyphenyl)-6-azabenzo[b]thiophene

A solution of 0.200 g (.69 mmol) of methyl3-(4-methoxyphenyl)methylthiopyridine-4-carboxylate in 2 mL of drytetrahydrofuran was added to a suspension of 83 mg (2.1 mmol) of 60%dispersion of sodium hydride in 2 mL of dry N,N-dimethylformamide. Themixture was stirred at room temperature for 3 hours, then poured ontoice water and acidified with glacial acetic acid. The solid material(product) was collected by filtration and the filtrate was extractedwith ethyl acetate. The ethyl acetate extract was dried, concentratedand combined with the solid precipitate that had been collected. Thismaterial was heated at reflux with 100 mg sodium acetate in 2 mL ofacetic anhydride for 2 hours, then was partitioned between ethyl acetateand water. The aqueous layer was washed with two portions of ethylacetate and the combined extracts were dried and concentrated. Theresidue was crystallized from methanol to afford 100 mg (48%) of whitecrystalline material, m.p. 141-142° C.

EXAMPLE 4 3-Acetoxy-2-phenyl-6-azabenzo[b]thiophene Step A: Preparationof 4-Cyano-3-phenyl-methylthiopyridine

Prepared from 4.3 g (31.1 mmol) of 3-chloro--4-cyanopyridine as inexample, Step A., except that benzylmercaptan was used instead ofp-methoxybenzylmercaptan to afford 6.1 g (87%) of a pale unstable oilthat was used directly in step B.

Step B: Preparation of 3-Phenylmethylthiopyridine-4-carboxylic acid

Prepared from 6.1 g of material from Step A by the procedure describedin example, Step B to afford 5.7 g (86%) of white crystalline material,m.p. 240°-5° C., (decomp.).

Step C: Preparation of Methyl 3-phenylmethylthiopyridine-4-carboxylate

A solution of 5.1 g (20 mmol) of 3-phenylmethylthiopyridine-4-carboxylicacid in 150 mL of methanol, 1.6 mL of 2,2-dimethoxypropane, and 5 mL ofsulfuric acid was heated at reflux for 18 hours. The solution wascooled, concentrated to 25 mL, then partitioned between ether and sodiumbicarbonate solution. The ether layer was washed with sodium bicarbonatesolution, then brine, then dried and concentrated to afford 5.0 g (96%)of white crystals, m.p. 79°-80° C.

Step D: Preparation of 3-Hydroxy-2-phenyl-6-azabenzo[b]thiophene

A solution of 4.8 g (19 mmol) of methyl3-phenylmethylthiopyridine-4-carboxylate in 10 mL of tetrahydrofuran wasadded to a slurry of 2.40 g (60 mmol) of 60% sodium hydride in 10 mL ofN,N-dimethylformamide and the resulting mixture was stirred at 60° C.for 3 hours. The solution was poured onto ice water and acidified withglacial acetic acid. The filtrate was collected to afford 1.6 g (38%) ofwhite solid.

Step E: Preparation of 3-Methoxymethoxy-2-phenyl-6-azabenzo[b]thiophene

A solution of 1.1 g (4.8 mmol) 3-hydroxy-2-phenyl-6-azabenzo[b]thiopheneand 0.116 g (4.8 mmol) of sodium hydride in 15 mL of tetrahydrofuran wasstirred at room temperature for 15 minutes. Then 0.37 mL (5.0 mmol) ofchloromethyl methyl ether was added and the solution was stirred at roomtemperature for 2 hours. The solution was partitioned between ether andwater and the ether extract was concentrated to afford 1.2 g (92%) ofwhite crystalline material, m.p. 55-56° C.

Step F: Preparation of7-(Hydroxyphenylmethyl)-3-methoxymethoxy-2-phenyl-6-azabenzo[b]thiophene

A solution of 0.43 g (3.7 mmol) of N,N,N',N'-tetramethylethylenediamineand 1.8 mL of 2.6M n-butyllithium was stirred at -20° for 1 hour, thencooled to -60°.

A solution of 1.0 g (3.7 mmol) of3-methoxy-methoxy-2-phenyl-6-azabenzo[b]thiophene in 5 mL of dry etherwas added and the solution was kept at -60° for 3 hours. The reactionwas quenched with 0.5 mL of benzaldehyde and allowed to warm to roomtemperature. The mixture was partitioned between ether and water and theaqueous layer was washed with ether. The combined extracts were driedand concentrated to an oil. Chromatography on silica gel (30% ethylacetate-hexane) afforded 0.62 g (44%) of a colorless oil, NMR (200 MHz,CDCl₃) δ3.4 (s, 3H), 5.0 (s, 2H), 5.95 (s, 1H, --OH), 7.2-7.8-(m, 12H),8.52 (d, J=6Hz, 1H), Mass Spec m/e 377 (M+).

Step G: Preparation of7-(Hydroxyphenylmethyl)-3-hydroxy-2-phenyl-6-azabenzo[b]thiophene

A solution of 0.61 g (1.8 mmol) of7-(hydroxyphenylmethyl)-3-methoxymethyl-2-phenyl-6-azabenzo[b]thiophenein 2.7 mL of 2M HCl and 2.7 mL of methanol was heated at reflux for 30minutes. The solution was cooled and partitioned between ethyl acetateand water. The ethyl acetate layer was dried and concentrated to afford0.50 g (93%) of white solid, m.p. 214°-215° C.

EXAMPLE 5 5-Aza-3-hydroxy-2-phenylbenzo[b]thiophene Step A: Preparationof 4-Benzylthionicotinic acid

To a stirred suspension of 1.55 g (0.01 mole) of 4-mercaptonicotinicacid (prepared by the process set forth in L. Katz, M. S. Cohen, and W.Schroeder, U.S. Pat. No. 2,824,876) in 20 mL of dry methanol cooled inice and stirred, was added 1.08 g (0.02 mole) of sodium methoxide. Theyellow solution was cooled in ice and 1.71 g (0.01 mole) of benzylbromide was added. Within one hour there was a new solid formation withloss of the yellow color. The reaction was kept for 2 more hours at roomtemperature, then most of the solvent was removed in vacuo. The solidresidue was taken up in 50 mL of water and acidified with an excess ofacetic acid to precipitate 2.45 g (100% of theory) of 4-(benzylthio)nicotinic acid which melted at 232°-234° C.

Step B: Preparation of Methyl 4-benzylthionicotinate

A suspension of 2.45 g (0.01 mole) of 4-benzylthionicotinic acid in 35mL of dry acetonitrile was treated with 1.52 g (0.01 mole) of1,8-diazabicyclo[5,4,0]under-7-ene (DBU). 1.7 g (0.01 mole) of methyliodide was added and stirring was continued for 7 hours. The reactionwas carefully diluted with water to crystallize 430 mg of methyl4-benzylthionicotinate which melted at 98°-99° C.

Anal.: Calc'd. C₁₄ H₁₃ NO₂ S. C=64.86, H=5.05, N=5.40. Found: C=65.11,H=5.28, N=5.65.

Step C: Preparation of 5-Aza-3-hydroxy-2-phenylbenzo[b]thiophene

A solution of 3.36 g (0.03 mole) of potassium tert-butoxide in 90 mL ofdry tetrahydrofuran was cooled to ice-temperature and stirred as 2.59 g(0.01 mole) of methyl 4-benzylthionicotinate was added. Theyellow-orange solution was stirred at ice-temperature for 15 minutes,then at room temperature overnight. Most of the tetrahydrofuran wasevaporated in vacuo. The residue was taken up in 100 mL of ice water andheated with an excess of acetic acid to obtain 1.91 g (84% of theory) of5-aza-3-hydroxy-2-phenylbenzo[b]thiophene, which was recrystallized fromN,N-dimethylformamide-ether giving a melting point of 260° C.

Anal.: Calc'd. for C₁₃ H₉ NOS. C=68.72, H=3.99, N=6.16. Found: C=68.34,H=4.09, N=6.18.

EXAMPLE 6 3-Acetyloxy-5-aza-2-phenylbenzo[b]thiophene

A mixture of 200 mg of 5-aza-3-hydroxy-2-phenylbenzo[b]thiophene, 10 mgof p-toluenesulfonic acid, and 2 mL of acetic anhydride was heated on asteam bath for three hours, then evaporated in vacuo. The residue wastaken up in 15 mL of ethyl acetate and 15 mL of ether, washed with 10 mLof 1% sodium bicarbonate solution, dried, concentrated to a smallvolume, and finally diluted with hexane to crystallize 155 mg (65% oftheory) of 3-acetyloxy-5-aza-2-phenylbenzo[b]thiophene; m.p. 101°-103°C.

Anal.: Calc'd. for C₁₅ H₁₁ NO₂ S. C=66.91, H=4.12, N=5.20. Found:C=66.96, H=4.19, N=5.53.

EXAMPLE 7 5-Aza-3-hydroxy-2-(4-methoxyphenyl)-benzo[b]thiophene Step A:Preparation of 4-(4-methoxybenzylthio)-nicotinic acid

A stirred and ice-cooled mixture of 788 mg (0.005 mole)4-chloronicotinic acid [prepared by the process set forth in W. C. J.Ross, J. Chem. Soc.(C), 1816 (1966)]and 771 mg (0.005 mole) of4-methoxybenzylmercaptan in 6 mL of dry N,N-dimethylformamide wastreated with 480 mg (0.012 mole) of 60% sodium hydride dispersion. Thereaction was stirred at room temperature for 4 hours during which athick solid formed, which was taken up in 75 mL of ice water. Afterextraction with 25 mL of hexane, the aqueous layer was acidified with2.5N hydrochloric acid to precipitate 4-(4-methoxybenzylthio)-nicotinicacid; yield 1.2 g (89% of theory), m.p. 230° C.

Step B: Preparation of Methyl 4-(4-methoxybenzylthio)nicotinate

A suspension of 2.2 g (0.008 mole) of 4-(4-methoxybenzylthio)-nicotinicacid in 30 mL of dry N,N-dimethylformamide was reacted with 1.78 g(0.011 mole) of 1,1'-carbonyldiimidazole. This was stirred at roomtemperature for 2 hours, then 0.5 mL of 4.3M sodium methoxide inmethanol and 5 mL of methanol. The reaction was stirred for 1 hour atroom temperature, then partitioned between 75 mL of ether and 30 mL ofwater. The ether layer was extracted with 2×30 mL of water, dried,concentrated to a small volume, and hexane added to crystallize methyl4-(4-methoxybenzylthio) nicotinate; yield 1.66 g (72% of theory), m.p.108°-110° C.

Anal.: Calc'd. for C₁₅ H₁₅ NO₃ S. C=62.28, H=5.23, N=4.84. Found:C=62.41, H=5.41, N=4.69.

Step C: Preparation of5-Aza-3-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of 672 mg (0.006 mole) of potassium tert-butoxide in 10 mL ofdry tetrahydrofuran was stirred at ice-temperature while 579 mg (0.002mole) of methyl 4-(4-methoxybenzylthio) nicotinate was added over 3minutes. The yellow solution was stirred for 10 more minutes atice-temperature, then at room temperature for 21/2 hours. The reactionwas diluted with 50 mL of ethyl acetate, and 0.5 mL of acetic acid wasadded. This was extracted with 3×30 mL of H₂ O. The organic layer wasdried and evaporated leaving 230 mg (45% of theory) of5-aza-3-hydroxy-2-(4-methoxyphenyl)-benzo[b]thiophene. Recrystallizationwas effected from tetrahydrofuran, m.p. 222°-225° C.

Anal.: Calc'd. for C₁₄ H₁₁ NO₂ S. C=65.37, H=4.31, N=5.44. Found:C=65.09, H=4.50, N=5.29.

5-Aza-3-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene can also beprepared by dissolving methyl 4-(4-methoxybenzylthio)nicotinate in 8 mLof dry N,N-dimethylformamide. This was stirred and cooled in ice as 120mg (0.005 mole) of NaH was added. After reaction was stirred at roomtemperature overnight, it was diluted with 100 mL of ice water anddecolorized with charcoal. An excess of acetic acid precipitated5-aza-3-hydroxy-2-(4-methoxyphenyl)benzo-[b]thiophene; yield 575 mg (75%of theory), m.p. 223°-225° C.

EXAMPLE 8 3-Acetyloxy-5-aza-2-(4-methoxyphenyl)benzo[b]thiophene

A mixture of 500 mg of5-aza-3-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene, 20 mg ofp-toluenesulfonic acid, and 8 mL of acetic anhydride was heated on asteam bath for 3 hours, then evaporated. The crystalline residue wastriturated with water, then recrystallized from methylenechloride-hexane to give 360 mg (62% of theory) of3-acetyloxy-5-aza-2-(4-methoxyphenyl)benzo[b]thiophene, m.p. 125°-127°C.

Anal.: Calc'd. for C₁₆ H₁₃ NO₃ S. C=64.21, H=4.38, N=4.68. Found:C=64.56, H=4.19, N=4.43.

EXAMPLE 9 3-Acetyloxy-2-(4-methoxyphenyl)-4-azabenzo[b]thiophene Step A:Preparation of Methyl3-(N,N-dimethylaminothiocarbamoyloxy)pyridine-2-carboxylate

A solution of 3.06 g (20 mmol) of methyl 3-hydroxypyridine-2-carboxylatein 15 mL of water was made basic with 1.12 g KOH. To this solution wasadded 3.2 g (26 mmol) of N,N-dimethylaminothiocarbamoyl chloride and thesolution was stirred at room temperature for 2 hours. The solution waspartitioned between benzene and water and the aqueous layer was washedwith two portions of water. The combined extracts were dried andconcentrated to afford 4.1 g of a white solid, m.p. 74°-75° C.

Step B: Preparation of Methyl3-(N,N-dimethylaminocarbamoylthio)pyridine-2-carboxylate

A solution of 2.9 g (12.1 mmol) of methyl3-(N,N-dimethylaminothiocarbamoyloxy)pyridine-2-carboxylate in 10 mL ofm-dimethoxybenzene was heated to 230° for 2 hours. The solution wascooled and filtered through silica with hexane to remove them-dimethoxybenzene. Then the silica was washed with acetone to afford2.4 g (83%) of a pale tan solid, m.p. 56°-58° C.

Step C: Preparation of Methyl3-(4-methoxyphenylmethylthio)pyridine-2-carboxylate

A solution of 1.20 g (5 mmol) of methyl3-(N,N-dimethylaminocarbamoylthio)pyridine-2-carboxylate in 5 mL ofmethanol and 1.5 mL (6 mmol) of 4.1M sodium methoxide methanol wasstirred at room temperature for 10 minutes. Then the solvent wasconcentrated and the residue was dissolved in 5 mL ofN,N-dimethylformamide and 5 mL of tetrahydrofuran. 0.936 g (6 mmol) ofp-methoxybenzylmercaptan was added and the solution was stirred at roomtemperature for 18 hours. The solution was partitioned between ether andwater and the aqueous layer was extracted with two portions of ether.The combined extracts were washed with brine, dried and concentrated.Recrystallization from methanol afforded 0.90 g (62%) of pale tanneedles, m.p. 99°-100° C.

Step D: Preparation of3-Acetyloxy-2-(4-methoxyphenyl)-4-azabenzo[b]thiophene

A solution of 0.65 g (2.24 mmol) of methyl3-(4-methoxyphenylmethylthio)pyridine-2-carboxylate in 5 mL of drytetrahydrofuran was added to a solution of 2.6 mmol of lithiumdiisopropylamide in dry tetrahydrofuran at -78° C. After 30 minutes thesolution was partitioned between ether and water and the aqueous layerwas saturated with NaCl and washed with two portions of dichloromethane.The combined extracts were dried and concentrated to an oil that wasdissolved in 2 mL of acetic anhydride and 200 mg of sodium acetate. Thissolution was heated at reflux for 1 hour, then partitioned between etherand water. The aqueous layer was washed with two portions of ether andthe combined extracts concentrated. The residue was chromatographed onHPLC (silica, 30% ethyl acetate-hexane) to afford 101 mg (15%) of whitecrystals, m.p. 146°-148° C.

C. Utility of the compounds within the scope of the invention

This invention also relates to a method of treatment for patients (ormammalian animals raised in the dairy, meat, or fur industries or aspets) suffering from disorders or diseases mediated by the inhibition ofthe oxidation of arachiodonic acid and/or leukotrienes, and gastricirritation or lesion. More specifically, this invention is directed to amethod of treatment involving the administration of one or more of theenzyme inhibitors of formula (I) as the active constituent.

Accordingly, a compound of Formula (I) can be used among other things toreduce pain and inflammatory conditions, including rheumatoid arthritis,osteoarthritis, gout, psoriasis, inflammatory bowel disease andinflammation in the eye that may be caused by ocular hypertension andmay eventually lead to glaucoma. It can also be used to correctrespiratory, cardiovascular, and intravascular alterations or disorders,and to regulate immediate hypersensitivity reactions that cause humanasthma and allergic conditions.

For the treatment of inflammation, arthritis conditions, cardiovasculardisorder, allergy, psoriasis, asthma, or other diseases mediated byprostaglandins and/or leukotrienes, a compound of Formula (I) may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intravascular injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, cattle, sheep, dogs, cats, etc., the compounds of the inventionare effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be forexample, (1) inert diluents such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; (2) granulating anddisintegrating agents such as corn starch, or alginic acid; (3) bindingagents such as starch, gelatin or acacia, and (4) lubricating agentssuch as magnesium stearate, stearic acid or talc. The tablets may beuncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotictherapeutic tablets for controlled release.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients may be

(1) suspending agents such as sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia;

(2) dispersing or wetting agents which may be

(a) a naturally-occurring phosphatide such as lecithin,

(b) a condensation product of an alkylene oxide with a fatty acid, forexample, polyoxyethylene stearate,

(c) a condensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethyleneoxycetanol,

(d) a condensation product of ethylene oxide with a partial esterderived from a fatty acid and a hexitol such as polyoxyethylene sorbitolmonooleate, or

(e) a condensation product of ethylene oxide with a partial esterderived from a fatty acid and a hexitol anhydride, for examplepolyoxyethylene sorbitan monooleate.

The aqueous suspensions may also contain one or more preservatives, forexample, ethyl or n-propyl p-hydroxybenzoate; one or more coloringagents; one or more flavoring agents; and one or more sweetening agentssuch as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide a palatable oral preparation. These compositions may bepreserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example, those sweetening, flavoring and coloring agentsdescribed above may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil such asolive oil or arachis oils, or a mineral oil such as liquid paraffin or amixture thereof. Suitable emulsifying agents may be (1)naturally-occurring gums such as gum acacia and gum tragacanth, (2)naturally-occurring phosphatides such as soy bean and lecithin,(3)esters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan monooleate, (4) condensation productsof said partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A compound of formula (I) may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable nonirritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the anti-inflammatory agents are employed.

Dosage levels of the order from about 1 mg to about 100 mg per kilogramof body weight per day are useful in the treatment of theabove-indicated conditions (from about 50 mg to about 5 gms. per patientper day). For example, inflammation is effectively treated andanti-pyretic and analgesic activity manifested by the administrationfrom about 2.5 to about 75 mg of the compound per kilogram of bodyweight per day (about 75 mg to about 3.75 gms per patient per day).

D. Biological Data Supporting the Utility of the Compounds Within theScope of the Invention.

The following is a summary of biological data from two bioassays. Thesedata serve to illustrate that the compound of formula (I), for example,7-aza-3-acetyloxy-2-phenyl-benzo[b]thiophene (compound A) and7-aza-3-acetyloxy-2-(4-fluorophenyl)-benzo[b]thiophene, (compound B) areuseful in the treatment of leukotriene mediated diseases.

1. Brewer's Yeast Hyperalgesia Assay*

In this assay, which is sensitive to inhibition by lipoxygenase andcyclooxygenase inhibitors, compounds of formula I reduced the painresponse induced by Brewer's yeast (Table 1a).

Groups of 10 female Sprague-Dawley rats, weighing 35-50 grams (CharlesRiver Breeding Laboratories), were fasted overnight prior to testing.For each animal, 0.1 ml of the edema-inducing Brewer's yeast suspension(5% homogenate in physiological saline) was injected into the righthindpaw. Pain threshold was measured by applying pressure to the plantarsurface of the hindpaw by means of a compressed air driven piston with a2 mm. tip. Testing was carried out 3, 4, and 5 hours after the yeastinjection. Compounds, prepared as homogenates in either 1%methylcellulose or aqueous vehicle, were administered orally 60 minutesbefore testing. A group of vehicle treated control animals was includedin each experiment. Squeak pressure thresholds were measured andrecorded for the compound and vehicle-treated groups of rats 3, 4, and 5hours after administration of the Brewer's yeast (60 minutes aftercompound treatment). The estimation of analgesia was as follows: 1. themean response pressure for the daily vehicle control group in the normaland inflammed foot was calculated; 2. for each compound treatment group,the number of animals with response pressures equal to or greater than25 mm Hg was noted. These animals were considered to be analgesic.

Following is data obtained using these various assays withrepresentative compounds of Formula I.

                  TABLE 1a                                                        ______________________________________                                        Effect of Compounds of Formula (I) on Yeast                                   Hyperalgesia in the Rat                                                        ##STR21##                                                                                                Dose     %                                        R         X.sup.1  X.sup.2  (mg/kg p.o.)                                                                           Inhibition                               ______________________________________                                        (CO)CH.sub.3                                                                            H        H        3        60                                       (CO)CH.sub.3                                                                            H        p-OCH.sub.3                                                                            3        10                                       H         H        p-OCH.sub.3                                                                            3        60                                       (CO)CH.sub.3                                                                            H        p-F      3        70                                       (CO)CH.sub.2 OCH.sub.3                                                                  H        H        3        50                                       (CO)CH.sub.3                                                                            6-Cl     H        3        40                                       (CO)CH.sub.3                                                                            6-OCH.sub.3                                                                            H        3        60                                       (CO)CH.sub.3                                                                            7-OCH.sub.3                                                                            H        3        50                                       (CO)CH.sub.3                                                                            7-CN     H        3        60                                       H         7-CN     H        3        50                                       ______________________________________                                    

2. Inhibition of PMN 5-lipoxygenase in the rat Methods:

PMN Isolation:

Male Sprague-Dawley rates under ether anesthesia were injected i.p. with8 mls of 12% aqueous sodium caseinate. After 15-24 hours the animalswere sacrificed with CO₂ and the peritoneal cavities were lavaged withEagles MEM with Earles salts and containing L-glutamine and 30 mM HEPES.The pH was adjusted to 7.4. The lavage fluid was centrifuged for 5minutes at 350×g at room temperature. The cells were resuspended infresh medium and filtered through lens paper. The cells were pelletedagain and reconstituted to a concentration of 1×10⁷ cells/ml with freshmedium.

Incubations:

The experiments were run as follows: 0.5μ of test compound in DMSO or0.5 μl DMSO alone was added to reaction tubes. 0.5 ml aliquots of thestirred PMN suspension maintained at 37° C. were then added. After 2minutes, 0.5 μl of 10 mM A23187 (final concentration=10 μM) or 5 μl ofDMSO was added and allowed to incubate for 4 additional minutes at 37°C. The reaction was stopped by the addition of 0.5 ml of cold methanol.The precipitated proteins were removed by centrifugation and thesupernatant fluid was analyzed via RIA or HPLC.

Radioimmunoassay determinations of LTB₄

Radioimmunoassays were performed using the dextran-coated charcoalbinding method as described by J. L. Humes in Methods for StudyingMononuclear Phagocytes (Eds. D. Adams et al.) p. 641, Academic Press,N.Y. (1981).

Aliquots, 2 μl, of the supernatant fluids were added to assay tubes andincubated for 10 minutes at 37° C. to remove methanol. Fifty μl oftissue culture medium M-199 containing 1 percentheat-inactivated-porcine serum was then added to each tube. Standardamounts of LTB₄ were also prepared in this medium so that 50 μl aliquotscontained 25-1000 pg. Antisera to LTB₄ was diluted 1:3000 with 10 mMpotassium phosphate, pH 7.3 containing 1 mM ethylenediaminetetraceticacid and 0.25 mM thimerasol (PET buffer). Aliquots, 100 μl, of thediluted antisera were added to both standard and unknown tubes andincubated at room temperature for 0.5 hour. (5,6,8,9,11,12,14,15-³H)-LTB₄ (Amersham, 150 Ci/mMol) was diluted with PET to a concentrationof 1 nCi/ml. Aliquots, 100 μl were added and the mixture incubated for 2hours at room temperature or alternatively overnight at 4° C. One ml ofdextran-coated charcoal solution is added to all tubes. Aftercentrifugation for 10 minutes at 1000×g the radioactivity in thesupernatant fluid was determined.

The dextran-coated charcoal removes the unbound ³ H-LTB₄. Therefore inthis procedure the antibody-bound-³ H-LTB₄ is measured. The RIA⁴determinations are performed on single samples.

                  TABLE 3                                                         ______________________________________                                        Effect of Compounds of formula (I) on                                         PMN-5-lipoxygenase                                                             ##STR22##                                                                    Position                         Dose   %                                     of N  R        X.sub.1    X.sub.2                                                                              mg/ml  Inhibition                            ______________________________________                                        5     (CO)CH.sub.3                                                                           4-CH.sub.3, 6-CH.sub.3                                                                   p-OCH.sub.3                                                                          0.3    75                                                                     0.1    45                                                                     0.03   4                                     7     (CO)CH.sub.3                                                                           H          p-CF.sub.3                                                                           1      100                                                                    0.3    100                                                                    0.1    61                                    7     "        H          p-F    0.1    100                                                                    0.037  49                                                                     0.01   24                                    7     H        H          "      0.3    100                                                                    0.1    99                                                                     0.037  88                                                                     0.01   32                                    5     (CO)CH.sub.3                                                                           H          p-OCH.sub.3                                                                          0.3    99                                                                     0.1    80                                                                     0.037  22                                    5     H        4-CH.sub.3, 6-CH.sub.3                                                                   H      1      99                                                                     0.3    90                                                                     0.1    43                                    6     H        H          p-OCH.sub.3                                                                          0.3    100                                                                    0.1    79                                                                     0.03   45                                    7     (CO)CH.sub.3                                                                           H          o-OCH.sub.3                                                                          0.3    100                                                                    0.1    73                                                                     0.03   33                                    6     H        4-CH.sub.3, 6-CH.sub.3                                                                   p-OCH.sub.3                                                                          1      93                                                                     0.3    54                                                                     0.1    30                                    7     H        H          m-OCH.sub.3                                                                          0.3    100                                                                    0.1    100                                                                    0.03   76                                    7     (CO)CH.sub.3                                                                           H          H      0.1    100                                                                    0.037  95                                                                     0.01   40                                    5     "        H          H      0.3    100                                                                    0.1    97                                                                     0.037  58                                    7     "        H          p-CN   0.3    100                                                                    0.1    77                                                                     0.037  39                                    5     "        H          p-OCH.sub.3                                                                          0.3    100                                                                    0.1    60                                    7     "        H          "      0.1    100                                                                    0.037  59                                    7     H        H          "      0.1    100                                                                    0.037  24                                    5     H        H          "      0.3    100                                                                    0.4    63                                    7     (CO)CH.sub.3                                                                           H          m-OCH.sub.3                                                                          0.3    100                                                                    0.1    97                                                                     0.037  52                                    7     H        H          H      0.1    100                                                                    0.012  32                                    7     (CO)CH.sub.3                                                                           4-Cl       H      1      100                                                                    0.1    32                                                                     0.037  22                                    7     (CO)CH.sub.3                                                                           H          p-OCH.sub.3                                                                          0.1    100                                                                    0.037  70                                    7     (CO)CH.sub.3                                                                           6-Cl       H      1      100                                                                    0.3    82                                                                     0.1    63                                    4     (CO)CH.sub.3                                                                           H          p-OCH.sub.3                                                                          1      100                                                                    0.3    73                                                                     0.1    21                                    7     H        t-Bu       H      1      98                                                                     0.3    98                                                                     0.1    53                                    7     (CO)CH.sub.3                                                                           t-Bu       H      0.03   23                                                                     1      95                                                                     0.3    70                                                                     0.1    34                                    ______________________________________                                    

    ______________________________________                                         ##STR23##                                                                    Position                         Dose   %                                     of N  R        X.sub.1    X.sub.2                                                                              mg/ml  Inhibition                            ______________________________________                                        7     H        H          H      1      98                                                                     0.3    94                                                                     0.1    39                                                                     0.03    0                                    7     (CO)CH.sub.3                                                                           H          H      1      95                                                                     0.3    55                                                                     0.1    31                                    ______________________________________                                    

    ______________________________________                                         ##STR24##                                                                    Position                       Dose   %                                       of N  R        X.sub.1         mg/ml  Inhibition                              ______________________________________                                        6     (CO)CH.sub.3                                                                           H               1      90                                                                     0.3    49                                                                     0.1    33                                      ______________________________________                                    

What is claimed is:
 1. A compound whichis3-acetoxy-2-(4-methoxyphenyl)-4-azabenzo[b]thiophene.
 2. A method forthe treatment of a 5-lipoxygenase mediated disease comprising theadministration to a mammalian species in need of such treatment aneffective amouunt of a compound of formula (I): ##STR25## or apharmaceutically acceptable salt thereof wherein R is (CO)CH₃ ; H; orloweralkyl;R¹ is phenyl substituted with X₂ ; X₁ is(a) H; (b) C₁₋₆alkyl; (c) halo; (d) halo-C₁₋₆ alkyl; (e) CN; (f) --(CO)OR³ ; or (g)--OC₁₋₆ alkyl; and X₂ is(a) H; (b) methylenedioxy; (c) haloC₁₋₆ alkyl;(d) halo; (e) CN; (f) --OC₁₋₆ alkyl, (g) --(CO)OR³ ; (h) C₁₋₆ alkyl; or(i) NO₂.
 3. The method of claim 2 wherein the active compoundis3-acetoxy-2-(4-methoxyphenyl)-4-azabenzo[b]thiophene.
 4. Apharamaceutical composition for treating a 5-lipoxygenase mediateddisease in mammalian species comprising a pharmaceutically acceptablecarrier and an effective amountof3-acetoxy-2-(4-methoxyphenyl)-4-aza-benzo[b]thiophene or apharmaceutically acceptable salt thereof.